Leukemia is a cancer of the blood-forming tissues characterized by a large increase in the numbers of white blood cells (leukocytes) in the circulation, bone marrow or other tissues. A number of different leukemias are classified according to the course of the disease and the predominant type of white blood cell involved. Leukemias are defined as either acute or chronic and as either myelogenous (from bone marrow) or lymphocytic (involving lymphocytes). These characteristics are used to designate almost all cases of leukemia as one of the following four types: acute myelogenous, acute lymphocytic, chronic myelogenous, and chronic lymphocytic leukemia. The two primary types of lymphocytes are B lymphocytes and T lymphocytes, or B cells and T cells.
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived B lymphocytes. Most of the circulating cells appear to be non-dividing and the clonal excess of B cells is mainly caused by defects that prevent programmed cell death rather than by alterations in cell cycle regulation. Glucocorticoids and other chemotherapeutic agents used clinically, including the nucleoside analogues cladribine (2-chloro-2′-deoxyadenosine) and fludarabine (9-β-D-arabino-2-fluoroadenine, used in the form of 5′-monophosphate), induce apoptosis (also called programmed cell death) in B-CLL lymphocytes, suggesting that apoptosis is the mechanism of their therapeutic action. Thus, fludarabine and other nucleosides are highly effective in the treatment of B-CLL, either alone or in combination with other agents. However, these nucleosides induce apoptosis of T cells. This induction represents an important adverse side-effect because it leads to immunosuppression.
B-cell chronic lymphocytic leukemia (B-CLL) is a particular case of a wider group of conditions that are usually referred as B-cell lymphoproliferative disorders, i.e. disorders and/or diseases related to an abnormal increase in B-cell number or function. Besides B-CLL, this group of conditions include, among others, splenic marginal zone lymphoma (SMZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), and Waldenström syndrome (WS). What is mentioned above illustrates that there is a need of new therapeutical agents for the treatment of B-cell lymphoproliferative disorders, and in particular of B-cell chronic lymphocytic leukemia (B-CLL).
Acadesine, which is also named 5-amino-1-β-D-ribofuranosyl-1H-imidazole-4-carboxamide, 5-aminoimidazole-4-carboxamide riboside, AICA riboside and AICAR, is a natural substance with CAS RN 2627-69-2 and with the following formula, where the numbering of hydroxyl groups is shown.

Acadesine 5′-monophospate, which is also named AICA ribotide and ZMP, has CAS RN 3031-94-5 and it is a natural occurring active metabolite of acadesine. Clinical studies in patients undergoing coronary artery bypass graft surgery demonstrate that treatment with acadesine before and during surgery can reduce early cardiac death and myocardial infarction (cf. e.g.: D. T. Mangano, Journal American Medical Association 1997, vol. 277, pp. 325-332). Phase III trials have been carried out with acadesine, indicating that it is safe when administered orally and intravenously. There are patents granted and/or patent applications published which relate to the use of acadesine for: preventing tissue damage due to decreased blood flow (cf. U.S. Pat. No. 4,912,092, U.S. Pat. No. 5,817,640); treating neurodegenerative conditions (cf. U.S. Pat. No. 5,187,162); preventing injury to the central nervous system (cf. U.S. Pat. No. 5,236,908); treating obesity (cf. WO 0193873 A1); treating type 2 diabetes (cf. WO 0197816 A1) and treating conditions associated with insulin resistance (cf. WO 0209726 A1). There are patents granted and/or patent applications published which relate to the use of acadesine 5′-monophosphate as flavouring material (cf. U.S. Pat. No. 3,355,301), anticholestermic/antihyperlipemic agent (cf. WO 9303734 A1), antiobesity agent (cf. WO 0193874 A1) and antidiabetic agent (cf. WO 0197816 A1). But nothing is mentioned or suggested in the art related to the use of acadesine, acadesine 5′-monophosphate or any of their prodrugs for treating leukemia and lymphoma.
It is known that acadesine is an apoptosis inhibitor of several cells. Thus, for instance, it is known that acadesine inhibits glucocorticoid-induced apoptosis in quiescent thymocytes, that acadesine inhibits apoptosis caused by serum deprivation in fibroblasts overproducing fructose 2,6-bisphosphate, and that acadesine inhibits ceramide-induced apoptosis in primary astrocytes. Therefore, should acadesine have any effect on lymphocytes apoptosis, acadesine would be expected to be an inhibitor of it.